Project Summary Myelomeningocele (MMC) is the most severe form of Spina Bifida, which results in significant and life-long neurological disabilities, impaired quality of life, and difficult medical management. Despite the huge clinical impact, currently available prenatal therapeutic methods are limited. In MMC, the spinal cord is exposed to the amniotic cavity through openings in the overlying vertebrae and skin resulting in progressive spinal cord damage during gestation. To prevent secondary damage to the spinal cord, surgical in utero closure of the MMC defect has been undertaken. However, the surgical procedures alone remain inadequate for restoration of neurological function. Therefore interventions to either aid prenatal surgical closure or act independently to minimize secondary pathology are required to reduce disabilities associated with MMC. Here, we propose to investigate the role of extracellular matrix components in pathological progression and development of prenatal treatment for MMC. In aim 1, we will evaluate the role of excessive deposition of chondroitin sulfate proteoglycans (CSPGs), a key component of the extracellular matrix in development of spinal cord damage and determine the efficacy of CSPG degradation in reducing the MMC-associated pathology and improvement of neurological function in a retinoic acid-induced rat model of MMC. Since it is well established that the opening of the overlying tissue contributes to spinal cord pathology, in aim 2, we will determine whether digestion of CSPGs at the MMC site combined with administration of hyaluronic acid (HA) and/or Mesenchymal Stem Cells (MSCs), will synergistically enhance repair of the MMC defects. Advancements in the treatment of MMC would ultimately reduce the burden on children and their families and improve their health and welfare.